Squamous cell carcinoma (SCC) accounts for approximately 96% or all oral cancers. SCC has a tendency to be locally invasive as well as to metastasize widely; the five-year survival rates are less than 50%. Tumor invasion and metastasis is a complex process involving multiple interactions between tumor cells and the extracellular matrix (ECM). Matrix components such as laminin and fibronectin have been studied extensively regarding their roles in tumor progression. However, other ECM components also play a role. In particular, we and others have observed that tenascin-C (TN-C) expression is upregulated in oral cancer. In this project we propose to investigate how the expression of TN-C and its receptor, alpha vbeta6, are regulated during oral SCC progression. TN-C is a large oligomeric glycoprotein that is transiently expressed during development and is involved in morphogenetic movements, tissue patterning, and tissue repair. TN-C contains multiple domains, both adhesive and anti- adhesive, that interact with cells, fibronectin, and other ECM molecules. There are different isoforms of the molecule, which result from alternative mRNA splicing. One receptor for TN-C is alphavbeta6. Several lines of evidence suggest that the alphav integrin subfamily is important for tumor growth, invasion, and metastasis. First, recent work has demonstrated that antagonists to alphavbeta3 inhibit tumor angiogenesis. Second, alphavbeta3 has been shown to be upregulated in vertically invasive melanoma. Third, alphavbeta6 was recently found to be neo-expressed in oral SCC, while absent from normal oral mucosa. We hypothesize that TN-C and alphavbeta6 play a role in the progression of oral cancer by acting as co-stimulatory modulators of tumor cell motility, invasion, or gene expression. The specific aims of this proposal are; (1) To assess the expression of tenascin-C and its receptor, alphavbeta6, as potential markers for invasive oral SCC. (2) To determine whether alterations in the expression of alphavbeta6 will modify the invasive behavior of oral SCC cells. (3) To evaluate different stages of tumor invasion, using an animal model, for differential expression of TN-C and alphavbeta6. These studies should enrich our understanding of how less- well-characterized matrix proteins like tenascin-C and the alphavbeta6 receptor contribute to oral cancer progression. Being able to identify those oral SCC tumors likely to be most invasive will help in selecting the most appropriate treatment modality and may improve the currently grim prognosis of patients with these tumors.